Oral Anticoagulation and the Devil You Don't Know vs the Devil You Do: Safety of NOACs vs Warfarin

Oral Anticoagulation and the Devil You Don't Know vs the Devil You Do: Safety of NOACs vs Warfarin Charles V. Pollack, Jr., M.A., M.D., FACEP, FAAEM, FAHA, FCPP Professor and Chairman Department of Emergency Medicine Pennsylvania Hospital University of Pennsylvania Philadelphia

Disclosure of Significant Relationships with Relevant Commercial Interests Charles V. Pollack, Jr., MA, MD No promotional activities Consultant to Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Durata, Luitpold Research support from Luitpold Pharmaceuticals, AstraZeneca

Oral Anticoagulation and the ED Initiate therapy for VTE (DVT and PE) Parenterally with unfractionated heparin, enoxaparin, dalteparin, fondaparinux, coupled with (and bridging to) warfarin Rivaroxaban (only FDA approved option to date, does not require bridging) Apixaban expected to be approved 2014, does not require bridging Dabigatran and edoxaban may be approved, do require bridging Initiate (or facilitate) anticoagulation for SPAF Mostly done by cardiologists or hospitalists Bridging not usually done Warfarin, rivaroxaban, apixaban, dabigatran Manage patients with ED presentations (including bleeding complications) who are being treated for VTE, on SPAF, or with mechanical valves, etc, with any of these agents

Evolving Approach to Anticoagulation Direct Xa Inhibitors Oral 2000s Direct thrombin Inhibitors Indirect Xa Inhibitors LMWH VKA Heparin Class of drug Courtesy F. Michota MD.

Inhibition of Vitamin K Dependent Coagulation Factors by Warfarin Intrinsic XII Extrinsic XI IX TF Protein C & S VIII Xa VII V II IIa Fibrinogen Fibrin Clot Weitz JI, et al. Chest. 2001;119(1 suppl):95s-107s; Gulseth MP, et al. Am J Health Syst Pharm. 2008;65(16):1520-1529.

Selective Factor Inhibition Novel Oral Anticoagulants Intrinsic XII Extrinsic XI IX TF Xa is an amplifica,on step Protein C & S VIII II Xa V IIa VII Rivaroxaban Apixaban Edoxaban Dabigatran (also inhibits clot- bound thrombin) Fibrinogen Fibrin Clot Blommel ML, et al. Am J Health-Syst Pharm. 2011;68:1506-1519; Gulseth MP, et al. Am J Health-Syst Pharm. 2008;65:1520-1529; Nutescu E. Am J Health-Syst Pharm. 2012;69:1113-1126; Palladino M, et al. Am J Hematol. 2012;87(suppl 1):127-132; Wittkowsky AK. Pharmacotherapy. 2011;31:1175 1191.

New Oral Anticoagulant Development Nonvalvular Atrial Fib and VTE In Development 2010 2011 2012 2013 2014 2015 2016 XARELTO (rivaroxaban) Bayer/JNJ QD/BID, fxa Inhibitor ORS 3Q11 AF 4Q11 DVT PE 4Q12 Pradaxa (dabigatran) Boehringer Ingelheim QD/BID, DT Inhibitor AF 3Q10 DVT PE App 4Q13 Eliquis (apixaban) BMS/Pfizer BID, fxa Inhibitor AF 4Q12 DVT PE App 4Q14 Lixiana (edoxaban) Daiichi Sankyo QD, fxa Inhibitor AF Antic 4Q14 DVT PE Antic 4Q14 Betrixaban Portola QD, fxa Inhibitor 7 Med Ill Antic 2Q16

NOACs in clinical trials SPAF, compared to warfarin: Dabigatran (150): superior efficacy all stroke, ischemic stroke; noninferior major bleed; superior all-cause mortality Rivaroxaban: noninferior efficacy all stroke, ischemic stroke; noninferior major bleed; noninferior all-cause mortality Apixaban: superior efficacy all stroke, noninferior ischemic stroke; superior major bleed; superior all-cause mortality All three had lower rates of intracranial bleeding compared to warfarin VTE treatment, compared to enox or UFH bridge to warfarin: Rivaroxaban: noninferior efficacy and safety Apixaban (not yet approved): noninferior efficacy, superior safety Dabigatran (not approved): noninferior efficacy and safety Edoxaban (not approved): noninferior efficacy, superior safety

Overview and Pharmacology Novel Oral Anticoagulants Apixaban 1-4 Dabigatran 1,5 Rivaroxaban 1,6 Drug class Direct factor Xa inhibitor Direct factor IIa inhibitor Direct factor Xa inhibitor Bioavailability 50% 3%-7% 80%-100% for 10 mg dose 66% for 20 mg dose Onset of anticoagulant effect Within 3 hours Within 2 hours Within 4 hours CYP metabolism 25% CYP3A4 No 30% CYP3A4, CYP2J2 Renal excretion 27% 80% 36% Half-life 12 hours 12-17 hours 5-9 hours Dosage form Tablet Capsule Tablet Dosing frequency BID BID BID or once daily CYP = cytochrome P450 1. Wittkowsky AK. Pharmacotherapy. 2011;31:1175-1191. 2. Zhang D, et al. Drug Metab and Disp. 2009;37:1738-1748. 3. Eliquis (apixaban). Available at: www.ema.europa.eu/ema/index.jsp? curl=pages/medicines/human/medicines/002148/human_med_001449.jsp&mid=wc0b01ac058001d124; 4. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company. December 2012; 5. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc. November 2012; 6. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2012.

Safety Concerns with NOACs Conundrum # 1 Patients on NOACs do not require routine anticoagulation monitoring. Conundrum # 2 Warfarin is safer than the NOACs because it can be reversed. Question: What is the best ED strategy for managing oral anticoagulant-related hemorrhage or intracranial bleed?

Conundrum # 1: Monitoring NOACs When dosed properly by indication and renal function, routine monitoring not required for NOACs used in treating VTE or providing SPAF At times, especially in ED when evaluating bleeding or bleeding concern in patients taking a NOAC, measurement of anticoagulation activity is desirable Standard PT/INR and aptt measures will not quantitatively assess anticoagulation with NOACs

Role of Coagulation Testing a for NOACs Apixaban 1-3 Dabigatran 1,2 Rivaroxaban 1-3 Ecarin clotting time (ECT) NA 5.2x baseline NA Anti-Xa activity NR NA 22% with 5 mg 68% with 30 mg Thrombin time (TT) NA 27x baseline NA Prothrombin time (PT) 2,4 Range: 1.5-2.0 There are no commercially available anti-xa assays calibrated for NOACs, only for UFH/LMWH Little effect at clinically relevant plasma concentration Range: 2.3-3.4 INR 1.5x baseline 1.8x baseline NR Activated partial thrombo-plastin time (aptt) 1.2x baseline 2.3x baseline 1.8x baseline HepTest NA NA 2.8x baseline Preferred Test Anti-Xa, mptt, HepTest ECT b, TT Anti-Xa c, PT d a Useful for assessing: compliance, drug interactions, overdose, use in renal and/or hepatic impairment; NOT to be used routinely for dose adjustments; b not readily available; c can use same assay as enoxaparin; d reagent dependent NA = not applicable; NR = not reported; mptt = modified prothrombin time 1. Eriksson BI, et al. Clin Pharmacokinet. 2009;48:1-22; 2. Barrett YC, et al. Thromb Haemost. 2010;104:1263-1271; 3. Kubitza D, et al. Eur J Clin Pharmacol. 2005; 61:873-880; 4. van Ryn J, et al. Thromb Haemost. 2010;103:1116-1127.

Assessing Intensity of Anticoagulation Effects Drug Present Quantitative Test Sensitivity: PT vs aptt No or Limited Effect Apixaban/Rivaroxaban? Chromogenic anti-factor Xa High sensitive INR Chromogenic anti-factor Xa PT > aptt ECT, TT Thrombin time Dabigatran? Dilute thrombin time or chromogenic ECT aptt > PT (point-of-care INR > central lab) Lindhoff-Last E, et al. Ther Drug Monit. 2010;32:673-679; Lindahl TL, et al. Thromb Haemost. 2011;105:371-378.; van Ryn J, et al. Am J Med. 2012;125:417-420; van Ryn J, et al. Thromb Haemost. 2010;103:1116-1127.

Conundrum # 2: Reversal of Warfarin It is inaccurate to refer to use of vitamin K as reversing warfarin-induced anticoagulation Use more accurate Anticoagulation with warfarin results from depletion of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C and S terminology: Administration of vitamin K allows liver to begin synthesizing these factors again REVERSE Endogenous repletion and correction of INR may take up to 24 h or longer, depending on patient s liver health and overall physiologic status If goal is hemostasis and not normal INR, exogenous repletion in addition to vitamin K must be provided RESUSCITATE AND REPLETE There is no analogue to Vitamin K treatment in patients taking NOACs Half-life of all NOACs significantly shorter than that of warfarin, so intensive support should be required for a shorter interval

Step 1: Resuscitate + Fresh-Frozen Plasma ABCs - Replete volume for BP (and, if needed, ICP) control - Type and cross-match - Stop interruptible blood loss (tamponade, endoscopy, interventional radiology) Decon - Consider activated charcoal - (dabigatran only) consider hemodialysis FFP 1 - Partially restores clotting factor levels - Blood typing required - Must be thawed at 30 o 37 o C for 20 30 min prior to use - Dosing is 15 ml/kg (infusion 3 6 h), which is a large amount of colloid volume Special considerations: Potential for circulatory overload Small risk of: viral transmission, passive alloimmune thrombocytopenia, anaphylaxis, septicemia 1. Cervera A, et al. J Neurol. 2012;259:212-224.

Effects of Repletion Agents on Anticoagulant Activity in an Ex-Vivo Model Measured Effect on Thrombin Generation: AUC, Peak, Time to Peak, and Lag Time Nonspecific Reversal Agent rfviia: NovoSeven 0.5,1.5,3 ug/ml apcc: FEIBA 0.25,0.5,1,2 U/mL 4-factor PCC a : Kanokad 0.25,0.5,1 U/mL Conclusions: If immediate reversal is needed, currently no clear evidence for any reversal agent clinically FEIBA effective for rivaroxaban ex-vivo, but higher doses are associated with more thrombin generation; clinically may cause more thrombosis Marlu R, et al. Thromb Haemost. 2012;108:217-224. Not tested Not tested Not tested Apixaban Dabigatran 150 mg + (lag time) + (lag time) + (increased AUC) Rivaroxaban 20 mg + (lag time) +++ (AUC, peak, lag time, and time to peak) ++ (strongly corrected AUC, modest peak) a PCCs contain significant quantities of factors II, IX, and X; 4-factor PCCs (approved but not yet available in the US) also contain factor VII rfviia = recombinant activated clotting factor VII

4-Factor PCC now FDA-Approved Repletes II, VII, IX, and X, plus proteins C and S (VII lacking in 3-factor PCC) Lower volume infusion required than FFP, with ~25x the factor concentration To date, much more study in treating warfarin-related bleeding than NOACs Reduces INR faster than FFP Restores factor levels faster than FFP 7x faster infusion time than FFP 87% reduction in volume of infusion compared to FFP Similar safety profile to FFP Sarode R, et al. Circulation. 2013 Aug 9. [Epub ahead of print].

Managing Bleeding in Patients Receiving Apixaban Apixaban No established way to reverse anticoagulant effect, which persists ~24h after last dose Because of high plasma protein binding, apixaban is not dialyzable Protamine sulfate and vitamin K do not affect anticoagulant activity No experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) No scientific rationale for reversal No experience with systemic hemostatics (desmopressin and aprotinin) Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or rfviia may be considered but have not been evaluated in clinical studies Activated oral charcoal reduces adsorption, thereby lowering apixaban plasma concentration Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2012.

Managing Bleeding in Patients Receiving Dabigatran Dabigatran Inhibits last step in coagulation cascade; any agent that stimulates this cascade or replaces coagulation factors proximal to thrombin will not compensate for the profound terminal hemostatic defect 1 Activated charcoal or gastric lavage early after ingestion 1 Completely adsorbs lipophilic drug in solution 1 PCC not known to mitigate anticoagulant effect 1 Consider activated PCC (very high doses) 2 rfviia recommended in PI for life-threatening bleeding 1,2 Triggers thrombin generation Has not been shown to reverse bleeding complications Has a very short half-life Expensive Associated with otherwise avoidable thromboembolism Acute hemodialysis for extreme cases 1 Only 35% of dabigatran protein bound 6 hours of dialysis decreased thrombin clotting time from 150 to 68 seconds 1. Schulman S, et al. Blood. 2012;119:3016-3023; 2. Ageno W, et al. Chest. 2012;141(suppl 1):e44s-e88s.

Managing Bleeding in Patients Receiving Rivaroxaban May be effective: Rivaroxaban All measurable anticoagulant effect reversed by 4-factor PCC in healthy male volunteers 1 can use 50 IU/kg in the case of acute major bleeding 3-factor PCC still available in US 1 Not dialyzable because highly protein bound (92%-95%) 2 Activated oral charcoal may be considered as it reduces absorption 3 1. Schulman S, et al. Blood. 2012;119:3016-3023; 2. Ageno W, et al. Chest. 2012;141(suppl 1):e44s-e88s; 3. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Nov. 2012.

Managing NOAC-related bleeding Practical Considerations Intracranial bleeds are significantly less common with NOACs than with warfarin The BEST strategy to treat bleeding is to prevent it Primum non nocere Half-lives of NOACs are short if the patient has normal renal function Appropriate patient selection PCCs should be used when clinically appropriate. The risk benefit of thrombosis must be considered Dialysis is indicated for severe bleeding with dabigatran Camm JA, et al. Eur Heart J. 2012;33:2719-2747; Schulman S, et al. Blood. 2012;119:3016-3023.

Summary NOACs are safer and more predictable than warfarin Shorter half-life Significantly lower rates of ICH than warfarin Cannot be readily assessed/monitored No oral anticoagulant-based major bleeding event can simply be reversed